COMPARATIVE ACTIVITY OF MELARSOPROL AND ARSENIC TRIOXIDE IN CHRONIC B-CELL LEUKEMIA LINES

Inorganic arsenic trioxide (As2O3) was recently shown to induce apopto sis in NE4 promyelocytic leukemic cells. We have investigated the effe cts of the organic arsenical, melarsoprol (a drug used for treatment o f trypanosomiasis), upon induction of apoptosis in cell lines represen tative of chronic B-cell lymphoproliferative disorders. An Epstein-Bar r virus (EBV)-transformed B-prolymphocytic cell line (JVM-2), an EBV-t ransformed B-cell chronic lymphocytic leukemia (B-CLL) cell line (183C LL), and one non-EBV-transformed B-CLL cell line (WSU-CLL) were used a s targets. Dose-response experiments with melarsoprol (10(-7) to 10(-9 ) mol/L) were performed over 96 hours. Unexpectedly, we found that mel arsoprol caused a dose- and time-dependent inhibition of survival and growth in all three cell lines. In contrast, As2O3 at similar concentr ations had no effect on either viability or growth. After 24 hours, al l three cell lines treated with melarsoprol (10(-7) mol/L) exhibited m orphologic characteristics of apoptosis. We also observed prominent co ncentration-dependent downregulation of bcl-2 mRNA after 24 hours of e xposure to melarsoprol in WSU-CLL, 183CLL, and JVM-2 cells. Decrease o f bcl-2 protein expression was also observed in all three cell lines, whereas As2O3 had no effect on this parameter, We conclude that melars oprol may inhibit the growth of lymphoid leukemic cell by promoting pr ogrammed cell death, Results of these studies suggest that melarsoprol shows promising therapeutic activity in these diseases, and a study t o evaluate clinical effects of this drug has been initiated. (C) 1997 by The American Society of Hematology.